Zenith Epigenetics · This presentation contains forward-looking statements that involve risks and...
Transcript of Zenith Epigenetics · This presentation contains forward-looking statements that involve risks and...
Zenith Epigenetics Advanced Epigenetic Technology March, 2019
Forward Looking Statement
Safe Harbor Statement. This presentation contains forward-looking statements that involve risks and uncertainties, which maycause actual results to differ materially from the statements made. For this purpose, any statements that are contained hereinthat are not statements of historical fact may be deemed to be forward- looking statements made pursuant to the safe harborprovisions of the Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, the words "believes,""anticipates," "plans," "intends," "will," "should," "expects," "projects," and similar expressions are intended to identify forward-looking statements. You are cautioned that such statements are subject to a multitude of risks and uncertainties that could causeactual results, future circumstances, or events to differ materially from those projected in the forward-looking statements. Theserisks include, but are not limited to, those associated with the success of research and development programs, the regulatoryapproval process, competition, securing and maintaining corporate alliances, market acceptance of the Company's products, theavailability of government and insurance reimbursements for the Company's products, the strength of intellectual property,financing capability, the potential dilutive effects of any financing, reliance on subcontractors and key personnel. The forward-looking statements are made as of the date hereof, and the Company disclaims any intention and has no obligation orresponsibility, except as required by law, to update or revise any forward-looking statements, whether as a result of newinformation, future events, or otherwise.
CONTACT: Donald J. McCaffreyChairman, President & CEO
Suite 300, 4820 Richard Road S.W. Calgary, AB, Canada T3E 6L1 Tel: (403) 254-9252, Fax:(403) 256-8495, http://www.zenithepigenetics.com
2
Corporate Profile and Milestones Leading to Pfizer Collaboration
Cash Raised 2014-2018
~US$50MM
@ US$1.00 & US$2.00 per unit based on pre-clinical results
Enterprise
Value est.
US$325MM
(US$2.50/Share) est.
Shares
Outstanding
129.6MM
142.0MM fully diluted
Cash BurnCurrent
US$2MM per quarter
Founded June 2013Spin out from Resverlogix
Corp. (TSX: RVX)2013
2016
2017
2017
June 2016 - Dosing first mCRPC patient with
ZEN-3694
Dec 2016 - Initiated combination study with Enzalutamide in mCRPC
patients
June 2017 - Announced issuance of US patent for
ZEN-3694
2018
Oct 2017 - Successful completion of single agent study with ZEN-3694
2016
Nov 2018 - Successful publications and 80 patients dosed
with ZEN-3694
3
Nov. 20/’18 -Pfizer clinical trial
collaboration announced
Advancing Development Pipeline
Indication 2019 2020
Metastatic Castration-resistant Prostate Cancer (mCRPC);(Fully Accrued)
Pfizer Collaboration: Triple Negative Breast Cancer (TNBC)
• Significant development progress with our lead product, ZEN-3694, a bromodomain and extra terminal domain inhibitor (BETi), currently in clinical development for combination treatment of solid tumors, including prostate and breast cancer
Phase 1b/2: Combination with PARPi in TNBC (N~50)
Combination expansion ZEN -3694 + enzalutamide; Patients progressed on abiraterone(N~15) or enzalutamide (N~25)
4
5
Epigenetics - The Mechanism Behind Our Approach
• The epigenetic code refers to modifications to chromatin components that regulate its activity
• Turning genes on or off is regulated by these modifications
• BET (Bromodomainand ExtraterminalDomain) proteins recognize these modifications and turn genes on/off
BET Inhibitors Target Resistance MechanismsSensitizing the Tumor to Existing Therapy
• Many of the escape resistance mechanisms to standard of care treatments involve BRD4
• BETi blocks BRD4 binding, resulting in inhibition of tumor oncogenes by disruption of super-enhancers
• Resistance to several standard of care treatments does not impede sensitivity to BETi, allowing for valuable combination therapy
Adopted from Clinical Cancer Research 2017, 23(7), 1647-55.
6
Combination Therapy: The Potential of BET Inhibition and ZEN-3694
Cancers Ecape Mechanism
Kinase-Signaling• PI3K (breast, CRPC)• RAF (melanoma)
Hormone-Modulaton• Androgen (CRPC)• Estrogen (breast cancer)
.
Immuno-Oncology
• Checkpoint Inhibitors (melanoma, NSCLC, bladder, H&N etc.)
DNA Repair•PARPi (Breast,
Ovarian, CRPC)BRD4
• BET inhibitors have the ability to work synergistically with other therapies overcoming resistance and enhancing the response to the combination, resulting in broader and extended use of existing therapies
The use of BETi is applicable to a number of cancers and therapies
ZEN-3694 synergizes with several standard of care cancer drugs
7
Zenith’s BETi program is Clinically Differentiated
8
• Conservative, suboptimal clinical strategy
• Poor PK/PD characterization
• Off target tox, CYP liabilities
• Thrombocytopenia DLT, require 1-2 weeks off
• Focused clinical strategy, leader in combination approach
• Good clinical exposure with target modulation, no CYP liabilities
• Safety profile allows continuous dosing, no thrombocytopenia
• On target tox profile
Zenith’s BETi (ZEN-3694)Other Clinical BETi
9
Our Synergistic Approach – Making Great Drugs Work Better & Longer
Ever-greening Key Existing
MarketsIncrease IP life
Differentiation from other
BETi Programs
Increase patient pool (responders)
Increase duration of
therapy
• Combination Therapy with ZEN-3694 represents a multi-$Bln addressable market
Current markets include: AR antagonists, PD-1/Pd-L1Mabs, CDK 4/6 inh., PARP inhibitors
Recent Zenith Publication Covers
10
Validation of Artificial Intelligence Program with Zenith’s Clinical Data
11
12
Prostate Cancer Program ReviewZEN-3694 Potential in Patients Developing mCRPC Resistance to Enzalutamide
ZEN-3694 works down
stream of current
therapies
ZEN-3694 works where resistance to existing lead
drugs, like Enzalutamide,
has evolvedThe combination of
ZEN-3694 and enzalutamide shows strong synergy and is expected to reduce the development of
resistance0
20
40
60
80
100
120
140
0.1 1 10 100
% p
rolif
era
tio
n c
om
par
ed
to
DM
SO-t
reat
ed
co
ntr
ol
concentration (uM)
Cell Viability in VCAP P3 + 0.1 nM R1881 Treated with various concentrations of ZEN003694 with Enzalutamide (3 Day)
3694
Enzalutamide + 0.1 uM 3694
Enzalutamide
Enzalutamide + 1 uM 3694
Enzalutamide + 10 uM 3694
13
Prostate Cancer Program ReviewPrincipal Investigators
Name Institution Comments
Eric Small, MDChief, Dept. of Medicine
Rahul Aggarwal, MDDevelopmental Therapeutics Specialist, Genitourinary Oncologist
University of California, San Francisco (UCSF)
Developed abiraterone - #2 CRPC drug, owned by J&J.
Howard Scher, MDChief, Genitourinary Oncology
Wassim Abida, MD, PhDMedical Oncologist
Memorial Sloan Kettering Cancer Center (MSKCC)
Developed enzalutamide - #1 CRPC drug, now owned by Pfizer. Developing ARN-509 for J&J
Joshi Alumkal, MDAssociate Professor
Oregon Health Sciences University (OHSU)
Expert in epigenetics in prostate cancer research
Allan Pantuck, MDProfessor, Dept. of Urology
University of California Los Angeles(UCLA)
Involved in enzalutamide and provenge development
Elizabeth Heath, MDProfessor, Dept. Hematology/Oncology
Karmanos (Wayne State) Genitourinary oncology specialist
Michael Schweizer, MDOncologist
University of WashingtonFred Hutchinson Cancer Center
Experience with AR antagonists
David M. Nanus, MDChief, Division of Hematology and Medical Oncology
Weill Cornell Medicine Genitourinary oncology specialist
Prostate Cancer Program ReviewPhase 2 Ongoing; Phase 1b Completed
Study Summary• Dose escalation completed, expansion cohorts enrolling• Robust target modulation at well tolerated doses, prolonged dosing without dose
interruption/reduction is tolerated• Clinical activity in patients progressing on abiraterone/enzalutamide• Significant response in primary abiraterone progressors (rPFS and PSA)• 100 patients dosed to date, fully accrued
14
Clinical data to be presented at American Association for Cancer Research 2019• Zenith will be the first to release clinical combination data with a BETi at a major scientific
meeting
Prostate Cancer Program Review: Combination Study Update Abiraterone Progressors
PR = partial response
15
Prostate Cancer Program Review: Promising DataDuration on ZEN-3694 + Enzalutamide by Patients that Progressed on Enzalutamide
• Expected time to radiographic progression (3-6 mo.) Attard et al. 2017** Target for ZEN-3694 +enzalutamide, 32 weeks
Median time to radiographic progression = 10.2 mo., similar for prior abiraterone or enzalutamide therapy
16
17
Prostate Cancer Program: Extensive Translational Medicine Plan Understand Responders/Non-Responders to Design Future Trials
Translational program designed for molecular profiling ARi resistant patients and effect of ZEN-3694 on resistant markers, potential correlation of response to molecular signature
Circulating tumor cells
Plasma
Whole blood
Tumor biopsyPrimary + Metastasis
RNA-sequencing
Immunohistochemistry• Oncology markers• Histology
• PD marker assay for target modulation
• Cancer immune panel• Target engagement
• Exploratory markers and cytokine panel
PBMCsPeripheral blood mononuclear cells
• Immuno Oncology markers, Tolerance Markers, T cell receptor sequencing
Whole blood
ZEN-3694
• Enumeration, markers, and signatures
• Expressed mutations and profiles• Pathway analysis• Immuno-oncology markers
Pfizer / Zenith Clinical Trial Collaboration
18
Pfizer / Zenith Clinical Trial Collaboration Summary
Objective • Show safety and activity of the combination in TNBC patients
Study design • Phase 1b dose escalation• Phase 2 Simon two step , open label non randomized
Patient Population
• TNBC: non germline BRCA1/2m, advanced metastatic, < 3 prior chemo therapy regimen, ER<10%, PR<10% and HER2-negative by IHC and/or FISH
Number of patients (N)
• N~ 9-12 for Dose escalation• Simon 2-stage design • Ho TNBC = 20% ORR, Target ORR = 40%, N= 17 1st stage, N= 17 for 1st stage, progress to second stage
if number of responders > 4, N=20 for second stage, 10% alpha, 90% power
Dose • ZEN-3694 starting dose: 72mg once daily
Duration • 6 months for dose escalation; 12 months for expansion cohorts (assuming 10 clinical sites)
Endpoints • Phase 1b: Safety, PK/PD, MTD, RP2D• Phase 2 TNBC: ORR, DOR, PFS• Exploratory: Explore biomarkers of activity and resistance
19
20
Pfizer / Zenith Clinical Trial CollaborationStrong Rational for BETi/PARPi Combination Therapy
Pfizer / Zenith Clinical Trial CollaborationProminent Clinical Sites and Investigators
Institution Investigator Background
MSKCC Mark Robson – Study Lead PI Ayca Gucalp - PI
Led OlympiAD trial
MD Anderson Jennifer Litton Led EMBRACA trial
Banner Health Lida Mina Investigator on Phase 1, 2 and 3 Talazoparib trials
University of Kansas Priyanka Sharma TNBC specialist
University of Penn Payal Shah - PI(Susan Domchek)
Talazoparib investigator, breast cancer specialist
Sarah Cannon Erika Hamilton Breast cancer specialist
Jules Bordet, Belgium Philippe Aftimos Led Merck and BI BETi trials
UZ Leuven, Belgium Kevin Punie Breast cancer specialist
VHIO, Spain Mafalda Oliveira Investigator on Gilead and GSK ER+ BETi trials
StartMadrid, Spain Valentina Boni Breast cancer specialist
21
Opportunity in Immuno Oncology:Strong Rationale for Checkpoint Combinations
BET bromodomain inhibition cooperates with PD-1 blockade to facilitate antitumor response in Kras-mutant non-small cell lung cancer.Adeegbe DO, et al. Cancer Immunol Res. 2018
22
Summary
Zenith is focused on ZEN-3694 combinations with SOC extending and expanding the value of existing therapeutics
• ZEN-3694 can be administered safely at doses that modulate BET targets
• Prostate/XTANDI combination: Promising clinical activity of ZEN-3694 + Enzalutamide in ARi resistant mCRPC patients
• Pfizer and Zenith collaboration (TNBC/PARPi): Ph. 1b/2 of ZEN-3694 + PARPi in TNBC (non germline-BRCA1/2m) initiated
• PD-1/PD-L1 combination with ZEN-3694 has compelling pre-clinical and clinical rationale
• ER+ Breast Cancer: Preclinical rationale to address resistance to CDK4/6 inhibitors; significant market
23
Leading epigenetic company translating bromodomain biology into impactful therapies